This project aims to identify abnormalities in brain function that contribute to dependence on drugs, and to offer leads in developing new treatment modalities. Our strategies have included evaluating the relationship between cocaine craving and brain metabolism as measured using the [F-18]flurodeoxyglucose-positron emission tomography (PET) method and electroencephalographic (EEG) signs of arousal; identifying a prefrontal lobe abnormality in substance abusers; and assessing how nicotine affects brain function. An extension of our PET study that linked visual cue-elicited cocaine craving to brain areas integrating emotional and cognitive aspects of memory assessed the spontaneous EEG in relation to drug-associated visual stimuli. Cocaine-related visual stimuli produced a greater reduction in alpha1 power, a sign of arousal, than did neutral visual stimuli. This EEG sign of arousal was negatively correlated with increases in brain metabolism. More importantly, there was a dissimilarity in the time courses of EEG arousal and craving, suggesting that self-reports of cue-elicited cocaine craving do not simply reflect increases in the state of arousal. A high-resolution magnetic resonance imaging study, measuring prefrontal lobe volumes in 25 polysubstance abusers and 14 normal volunteers, found that the total volume of the prefrontal lobe was significantly smaller in substance abusers. When the prefrontal lobe was segmented for gray and white matter, the deficit was seen as a smaller volume of gray but not white matter. These results indicate that hypoplasia and/or atrophy in the prefrontal lobe accompany polysubstance abuse. A new study is evaluating the effects of nicotine on brain function, as measured by PET with [O-15]H2O. Regional cerebral blood flow activation during a working memory task was assessed in abstinent (12 h) nicotine-dependent smokers and non-dependent controls. In nicotine-dependent smokers (n = 6), memory performance seemed to be mediated by different neural substrates than those in controls (n = 6), suggesting that chronic exposure to nicotine alters cognitive strategies or neural systems subserving memory. Regional activation related to memory load was increased by nicotine in controls, but only slightly so in smokers.